This invention relates to novel substituted benzimidazol-2-ones. More particularly, the compounds of the present invention modulate the binding of the peptide hormone vasopressin and neuropeptide Y to their respective receptors and are therefore useful for treating conditions involving increased vascular resistance, cardiac insufficiency, and disorders of energy metabolism.
Vasopressin is a nonapeptide hormone that is secreted primarily from the posterior pituitary gland. The hormone effects its actions through the vascular V-1 and renal V-2 receptor subtypes. The functions of vasopressin include contraction of uterine, bladder, and smooth muscle; stimulation of glycogen breakdown in the liver; induction of platelet aggregation; release of corticotropin from the anterior pituitary and stimulation of renal water reabsorption. As a neurotransmitter within the central nervous system (CNS), vasopressin can affect aggressive behavior, sexual behavior, the stress response, social behavior and memory. The V-1a receptor mediates central nervous system effects, contraction of smooth muscle and hepatic glycogenolytic effects of vasopressin, while the V-1b receptor mediates anterior pituitary effects of vasopressin. The V-2 receptor, presumably found only in the kidney, effects the antidiuretic actions of vasopressin via stimulation of adenylate cyclase.
Elevated plasma vasopressin levels appear to play a role in the pathogenesis of congestive heart failure (P. A. Van Zwieten, Progr. Pharmacol. Clin. Pharmacol. 1990, 7, 49). As progress toward the treatment of congestive heart failure, nonpeptide vasopressin V-2 receptor antagonists have induced low osmolality aquaresis and decreased peripheral resistance in conscious dogs with congestive heart failure (H. Ogawa, J. Med. Chem. 1996, 39, 3547). In certain pathological states, plasma vasopressin levels may be inappropriately elevated for a given osmolality, thereby resulting in renal water retention and hyponatremia. Hyponatremia, associated with edematous conditions (cirrhosis, congestive heart failure, renal failure), can be accompanied by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Treatment of SIADH-compromised rats with a vasopressin V-2 antagonist has corrected their existing hyponatremia (G. Fujisawa, Kidney Int. 1993, 44(1), 19). Due in part to the contractile actions of vasopressin at its V-1 receptor in the vasculature, vasopressin V-1 antagonists have reduced blood pressure as a potential treatment for hypertension as well. Thus, vasopressin receptor antagonists are useful as therapeutics in the conditions of hypertension, congestive heart failure/cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, and water retention.
Several non-peptide arginine vasopressin (AVP) antagonists have been reported. One of the V1a selective antagonists is known as OPC 21268 (see J. Donald Albright and P. S. Chan, Current Pharm. Design, 1997, 3, 615-632), 
which is stated to be only active in rat with no activity when tested for binding to human V1a receptor.
U.S. Pat. Nos. 5,849,780 and 5,585,394, both to Malta et. al., show compounds of the following structures, respectively: 
Sr-121463A is stated to be a potent selective orally active V2 receptor antagonist.
Neuropeptide Y (NPY) is a 36 residue, amidated polypeptide widely present in both the central and peripheral nervous systems. It is also present in the cardiovascular system, platelets, endothelium, adrenal medulla, pancreas, kidney and other organs. NPY binds to a number of G-protein coupled receptors such as Y1, Y2, and Y3. The Y1 receptor is stimulated by NPY or PYY (Peptide YY) and believed to be the major vascular receptor. The Y2 receptor is stimulated by C-terminal fragments of NPY or PYY and is abundantly expressed both centrally and peripherally. Present in adrenal medulla, heart, and brain stem, Y3 is exclusively responsive to NPY. Other subtypes of this receptor family are also known to exist. NPY has a number of biological effects. Intranasal administration of NPY reduces nasal airway resistance and vascular permeability. NPY also plays an important role in modulating the cardiovascular system, behavior, anxiety and the secretion of certain hormones; it contributes to the central and peripheral control of blood pressure, the regulation of feeding behavior, obesity, diabetes and psychiatric disorders.
It has been reported that Y1 agonists cause an increase in blood pressure as well as feeding behavior. Y2 agonists/antagonists, on the other hand, can modulate neurotransmitter release.
The present invention is directed to compounds represented by the following Formula I: 
wherein
A is aryl or heteroaryl having 0-4 heteroatoms selected from N, O, and S;
X is selected from S, O, NH, and NCN;
Y is S or O;
R1 is 1-3 groups selected from hydrogen, alkyl, substituted alkyl, halogen, nitro, methylenedioxy, nitrile, xe2x80x94ORa, xe2x80x94NHRa, xe2x80x94NRaRb, xe2x80x94S(O)pRa, xe2x80x94N(Ra)C(O)Rb, xe2x80x94C(O)ORa, xe2x80x94C(O)NRaRb, xe2x80x94SO2NRaRb, xe2x80x94N(Ra)SO2Rb, N(Ra)C(O)NRa, and NHCOORa, wherein Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl;
R2 is selected from hydrogen, alkyl, and substituted alkyl;
R3 is selected from hydrogen, alkyl, substituted alkyl, benzhydryl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, xe2x80x94C(O)ORc, and xe2x80x94C(O)NRcRd, wherein Rc and Rd are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, or NRcRd may be taken together to form a group selected from heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;
R4 and R5 are independently selected from hydrogen, alkyl, alkyl substituted with aryl or heteroaryl, phenyl, substituted phenyl, or R4 and R5 are non-existent when n is 0;
p is from 0 to 2;
n is 0 or 1; and
m is 0 or 1, with the proviso that when m is 0, X is O, and R3 is selected from heteroaryl, substituted heteroaryl, xe2x80x94C(O)ORc, and xe2x80x94C(O)NRcRd wherein Rc and Rd are independently selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, or NRcRd may be taken together to form a group selected from heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, then n is 0;
or an optical isomer, enantiomer, diastereomer, racemate thereof, or a pharmaceutically acceptable salt thereof.
The compounds of the present invention are vasopressin receptor antagonists which are useful in disease states of inner ear disorders, aggression, obsessive-compulsive disorders, hypertension, hyperglycemia, dysmenorrhea, congestive heart failure/cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, cerebral edema and ischemia, stroke, thrombosis, water retention, nephrotic syndrome, central nervous injuries, diabetes, anxiety, depression, stress, and/or Cushing""s disease.
The compounds of the present invention are also Neuropeptide Y modulators which are useful in disease states of hypertension, congestive heart failure/cardiac insufficiency, obesity, diabetes, anorexia, hyperglycemia, anxiety, depression, asthma, memory loss, sexual dysfunction, and disorders of sleep and other circadian rhythms.
An embodiment of the invention is a method of treating a condition associated with vasopressin receptor activity or Neuropeptide Y receptor activity in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions thereof.
An embodiment of the invention is a method of treating a condition associated with Neuropeptide Y receptor activity in a subject in need thereof comprising administering to the subject a therapeutically effective amount of any of the compounds or pharmaceutical compositions thereof.
Another embodiment of the invention is a method of inhibiting the onset of a condition associated with vasopressin receptor activity or Neuropeptide Y receptor activity in the subject, which comprises administering to the subject a prophylactically effective dose of a pharmaceutical composition of a compound of Formula I.
Further exemplifying the invention is the method of treating obesity, diabetes, anxiety, depression, asthma, or hypertension, wherein the therapeutically effective amount of the compound is about 1 to about 30 mg/kg/day.
Still further exemplifying the invention is the method of inhibiting the onset of obesity, diabetes, anxiety, depression, asthma, or hypertension, wherein the prophylactically effective amount of the compound is about 1 to about 30 mg/kg/day.
An additional illustration of the invention is a method of treating a condition selected from aggression, obsessive-compulsive disorders, hypertension, dysmenorrhea, congestive heart failure/cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, edema, ischemia, stroke, thrombosis, water retention, nephrotic syndrome, central nervous injuries, obesity, anorexia, hyperglycemia, diabetes, anxiety, depression, asthma, memory loss, sexual dysfunction, disorders of sleep and other circadian rhythms, and Cushing""s disease. Preferably, the therapeutically effective amount of the compound administered for treating any of these conditions is about 1 to about 30 mg/kg/day.
Also included in the invention is the use of any of the compounds described above for the preparation of a medicament for treating a condition selected from aggression, obsessive-compulsive disorders, hypertension, dysmenorrhea, congestive heart failure/cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, edema, ischemia, stroke, thrombosis, water retention, nephrotic syndrome, central nervous injuries, obesity, anorexia, hyperglycemia, diabetes, anxiety, depression, asthma, memory loss, sexual dysfunction, disorders of sleep and other circadian rhythms, and Cushing""s disease.
The present invention provides nonpeptide substituted benzimidazol-2-one compounds which are useful as antagonists of vasopressin and/or modulators of Neuropeptide Y activity. Particularly, these compounds inhibit the binding of vasopressin to V-1a, V-1b, and/or V-2 receptors as well as the binding of Neuropeptide Y to the varied Neuropeptide Y receptors. The compounds of this invention also inhibit vasopressin-induced intracellular calcium mobilization in transfected HEK-293 cells expressing human V-1a or V-1b receptors and/or inhibit vasopressin-induced cAMP accumulation in transfected HEK-293 cells expressing human V-2 receptors.
More particularly, the present invention is directed to compounds of Formula I: 
wherein
A is aryl or heteroaryl having 0-4 heteroatoms selected from N, O, and S;
X is selected from S, O, NH, and NCN;
Y is S or O;
R1 is 1-3 groups selected from hydrogen, alkyl, substituted alkyl, halogen, nitro, methylenedioxy, nitrile, xe2x80x94ORa, xe2x80x94NHRa, xe2x80x94NRaRb, xe2x80x94S(O)pRa, xe2x80x94N(Ra)C(O)Rb, xe2x80x94C(O)ORa, xe2x80x94C(O)NRaRb, xe2x80x94SO2NRaRb, xe2x80x94N(Ra)SO2Rb, N(Ra)C(O)NRa, and NHCOORa, wherein Ra and Rb are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteroaryl;
R2 is selected from hydrogen, alkyl, and substituted alkyl;
R3 is selected from hydrogen, alkyl, substituted alkyl, benzhydryl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, substituted heterocyclyl, xe2x80x94C(O)ORc, and xe2x80x94C(O)NRcRd, wherein Rc and Rd are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, or NRcRd may be taken together to form a group selected from heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl;
R4 and R5 are independently selected from hydrogen, alkyl, alkyl substituted with aryl or heteroaryl, phenyl, substituted phenyl, or R4 and R5 are non-existent when n is 0;
p is from 0 to 2;
n is 0 or 1; and
m is 0 or 1, with the proviso that when m is 0, X is O, and R3 is selected from heteroaryl, substituted heteroaryl, xe2x80x94C(O)ORc, and xe2x80x94C(O)NRcRd wherein Rc and Rd are independently selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, or NRcRd may be taken together to form a group selected from heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, then n is 0;
or an optical isomer, enantiomer, diastereomer, racemate thereof, or a pharmaceutically acceptable salt thereof.
The substituted benzimidazol-2-one compounds of the present invention are vasopressin receptor antagonists. In a preferred embodiment, the compounds are orally active. As demonstrated by the results of the pharmacological studies described hereinafter, the compounds show the ability to block vasopressin binding to recombinant V-1a, V-1b, and/or V-2, and therefore are useful as therapeutics in or prophylactics against conditions such as inner ear disorders, aggression, obsessive-compulsive disorders, hypertension, hyperglycemia, dysmenorrhea, congestive heart failure/cardiac insufficiency, coronary vasospasm, cardiac ischemia, liver cirrhosis, renal vasospasm, renal failure, edema, ischemia, stroke, thrombosis, water retention, nephrotic syndrome, stress, and central nervous injuries.
The substituted benzimidazol-2-one compounds of the present invention are also Neuropeptide Y receptor modulators. In a preferred embodiment, the compounds are orally active. The compounds show the ability to modulate the binding of Neuropeptide Y to Neuropeptide Y receptors, and therefore are useful as therapeutics in or prophylactics against conditions such as obesity, anorexia, diabetes, hyperglycemia, anxiety, depression, asthma, memory loss, sexual dysfunction, and disorders of sleep and other circadian rhythms.
In particular, compounds of Formula I, wherein A is phenyl or substituted phenyl are embodiments of the present invention. Compounds of Formula I wherein X is S or N are further embodiments of the present invention.
Compounds of Formula I, wherein R2 is alkyl substituted with one or more groups selected from cycloalkyl, aryl, xe2x80x94NHC(NH)NRcRd, xe2x80x94NRcRd, xe2x80x94C(O)ORc, xe2x80x94ORc, xe2x80x94NHC(O)Rc, and xe2x80x94C(O)NRcRd, wherein Rc and Rd are independently selected from hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, or NRcRd may be taken together to form a group selected from heteroaryl, substituted heteroaryl, heterocyclyl, and substituted heterocyclyl, are also embodiments of the present invention. More particularly X is S and R3 is aryl or substituted aryl.
Compounds of Formula I, wherein A is aryl, X is S, R2 is substituted alkyl, m is 0, n is 1, R3 and R4 are both aryl, and R5 is H, are particular embodiments of the present invention.
More specifically, the following compounds are particular embodiments of the present invention:
1-piperidinecarbothioamide, 4-[3-[3-(cyclohexylmethylamino)propyl]-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;
1-piperidinecarbothioamide, 4-[3-[3-(3,5-dimethyl-1-piperidinyl)propyl]-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;
1-piperidinecarbothioamide, 4-[2,3-dihydro-2-oxo-3-[3-(1-piperidinyl)propyl]-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;
1-piperidinecarbothioamide, 4-[3-[3-(dimethylamino)propyl]-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;
1-piperidinecarbothioamide, 4-[2,3-dihydro-2-oxo-3-[3-(1-pyrrolidinyl)propyl]-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;
1-piperidinecarbothioamide, 4-[3-(2-aminoethyl)-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;
1-piperidinecarbothioamide, 4-[3-[3-[(aminoiminomethyl)amino]propyl]-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;
1-piperidinecarbothioamide, 4-[3-(4-aminobutyl)-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;
1-piperidinecarbothioamide, 4-[3-(4-aminobutyl)-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-[(4-chlorophenyl)phenylmethyl]-;
1-piperidinecarbothioamide, 4-[3-(3-aminopropyl)-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;
1-piperidinecarbothioamide, 4-[3-[2-(diethylamino)ethyl]-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl]-N-(diphenylmethyl)-;
phenylalanine, N-[[4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]carbonothioyl]-, methyl ester; and
1-piperidinecarbothioamide, 4-(2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-N-(1,2-diphenylethyl)-.
The compounds of Formula I may be prepared from readily available starting materials in accordance with various known synthetic routes.
The present invention is also directed to intermediates of Formulae 4 and 5, 
wherein P is hydrogen or a protecting group such as benzyl (Bn) or BOC (t-butyloxycarbonyl), i is an integer from 1 to 8, and A and R1 are as described hereinabove.
The compounds of the present invention may also be present in the form of a pharmaceutically acceptable salt or salts. For use in medicine, the salt or salts of the compounds of this invention refer to non-toxic xe2x80x9cpharmaceutically acceptable salt or salts.xe2x80x9d Other salts may, however, be useful in the preparation of compounds according to this invention or of their pharmaceutically acceptable salts. Representative organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benezenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid. Representative basic/cationic salts include, but are not limited to, benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, or zinc.
Where the compounds according to this invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds possess two or more stereogenic centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.
The term xe2x80x9csubjectxe2x80x9d as used herein, refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
As used herein, xe2x80x9ctreatingxe2x80x9d a disorder means eliminating or otherwise ameliorating the cause and/or effects thereof. To xe2x80x9cinhibitxe2x80x9d or xe2x80x9cinhibitingxe2x80x9d the onset of a disorder means preventing, delaying or reducing the likelihood of such onset.
Methods are known in the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition. The term xe2x80x9ctherapeutically effective amountxe2x80x9d as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated. The term xe2x80x9cprophylactically effective amountxe2x80x9d refers to that amount of active compound or pharmaceutical agent that inhibits in a subject the onset of a disorder as being sought by a researcher, veterinarian, medical doctor or other clinician, the delaying of which disorder is mediated by the reduction of increased vascular resistance.
Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.
Unless otherwise noted, xe2x80x9calkylxe2x80x9d as used herein, whether used alone or as part of a substituent group, include straight and branched chains having 1 to 8 carbon atoms, as well as cycloalkyl groups containing 3 to 8 ring carbons and preferably 5 to 7 ring carbons, or any number within these ranges. For example, alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl and 2-methylpentyl. Alkoxy radicals are oxygen ethers formed from the previously described straight or branched chain alkyl groups. An alkyl as used herein may be substituted with one or more independent groups including, for example, cycloalkyl, amino, substituted amino, halogen, hydroxy, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, and/or unsubstituted or substituted aryl such as phenyl or benzyl, xe2x80x94C(O)ORe, ORe, xe2x80x94OC(O)Re, xe2x80x94C(O)NReRf, xe2x80x94N(Re)C(O)Rf, xe2x80x94N(Re)C(O)NRf, or xe2x80x94NHC(NH)NReRf wherein Re and Rf are independently selected from hydrogen, alkyl, halogen, hydroxy, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, and/or unsubstituted or substituted aryl.
xe2x80x9cHeterocyclylxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d is a 3- to 8-member saturated or partially saturated single or fused ring system which consists of carbon atoms and from one to three heteroatoms selected from N, O and S. The heterocyclyl group may be attached at any heteroatom or carbon atom, which results in the creation of a stable structure. Examples of heterocyclyl groups include, but are not limited to morpholine, thiomorpholine, pyrazolidine, pyrazoline, pyrrolidine, piperidine, and piperazine. xe2x80x9cHeterocyclylxe2x80x9d or xe2x80x9cheterocyclexe2x80x9d may be substituted with one or more independent groups including, but not limited to, H, halogen, oxo, OH, alkyl, substituted alkyl, amino, carboxyl, alkylcarboxyl, and alkoxy.
The term xe2x80x9cArxe2x80x9d or xe2x80x9carylxe2x80x9d as used herein, whether used alone or as part-of a substituent group, refers to an aromatic group such as phenyl, naphthyl, and fluorenyl. When the Ar or aryl group is substituted, it may have one to three substituents which are independently selected from C1-C8 alkyl, substituted C1-C8 alkyl (e.g., trifluoromethyl), C1-C8 alkoxy, substituted C1-C8 alkoxy (e.g., trifluoromethoxy), halogen, cyano, hydroxy, amino, substituted amino (e.g., C1-C4 alkylamino or C1-C4 dialkylamino wherein the alkyl groups can be the same or different), nitro, carboxyl, and unsubstituted, mono-, di- or tri-substituted phenyl wherein the substituents on the phenyl are independently selected from aryl, C1-C8 alkyl, C1-C8 alkoxy, substituted C1-C8 alkyl, fluorinated C1-C8 alkoxy, halogen, cyano, hydroxy, amino, nitro, carboxyl, alkylcarboxyl, alkylamino, dialkylamino and heteroaryl. xe2x80x9cPhxe2x80x9d or xe2x80x9cPHxe2x80x9d denotes phenyl. xe2x80x9cBnxe2x80x9d denotes benzyl.
The term xe2x80x9cheteroarylxe2x80x9d as used herein represents a stable five or six-membered monocyclic or bicyclic aromatic ring system which consists of carbon atoms and from one to three heteroatoms selected from N, O and S. The heteroaryl group may be attached at any heteroatom or carbon atom, which results in the creation of a stable structure. Examples of heteroaryl groups include, but are not limited to pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, thiophenyl, furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, indolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl or quinolinyl. Prefered heteroaryl groups include pyridinyl, thiophenyl, furanyl, quinolinyl, and 
When the heteroaryl group is substituted, the heteroaryl group may have one to three substituents which are independently selected from C1-C8 alkyl, substituted C1-C8 alkyl, halogen, aryl, heteroaryl, alkoxy, alkylamino, dialkylamino, arylamino, nitro, carboxyl, alkylcarboxyl, and hydroxy.
The term xe2x80x9cacylxe2x80x9d as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group.
The term xe2x80x9cAcxe2x80x9d as used herein, whether used alone or as part of a substituent group, means acetyl.
The term xe2x80x9chalogenxe2x80x9d shall include iodine, bromine, chlorine and fluorine.
Whenever the term xe2x80x9calkylxe2x80x9d, xe2x80x9cacylxe2x80x9d, or xe2x80x9carylxe2x80x9d or either of their prefix roots appear in a name of a substituent (e.g., aralkyl, dialkylamino), it shall be interpreted as including those limitations given above for xe2x80x9calkylxe2x80x9d, xe2x80x9cacylxe2x80x9d, and xe2x80x9caryl.xe2x80x9d Designated numbers of carbon atoms (e.g., C1-C6) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.
It is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.
As used herein, the term xe2x80x9ccompositionxe2x80x9d is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.
The present invention therefore provides a method of treating vascular resistance disorders in a subject in need thereof which comprises administering any of the compounds as defined herein in a quantity effective to treat vascular resistance disorders. The compound may be administered to a patient by any conventional route of administration, including, but not limited to, intravenous, oral, subcutaneous, intramuscular, intradermal and parenteral.
The present invention also provides pharmaceutical compositions comprising one or more compounds of this invention in association with a pharmaceutically acceptable carrier.
To prepare the pharmaceutical compositions of this invention, one or more compounds of Formula I or salt thereof of the invention as the active ingredient, is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed. Thus, for liquid oral preparations, such as for example, suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral preparations such as, for example, powders, capsules, caplets, gelcaps and tablets, suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques. For parenterals, the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included. Injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above. The pharmaceutical compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, powder, injection, suppository, teaspoonful and the like, of from about 1 mg to 30 mg/kg and may be given at a dosage of from about 1 to 30 mg/kg/day (preferred 3 to 15 mg/kg/day). The dosages, however, may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. The use of either daily administration or post-periodic dosing may be employed.
Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the composition may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of material can be used for such enteric layers or coatings, such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include, aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions, include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
Where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a stereogenic HPLC column.
During any of the processes for preparation of the compounds of the present invention, it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley and Sons, 1999. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
This invention will be better understood by reference to the schemes and examples that follow, but those skilled in the art will readily appreciate that these are only illustrative of the invention as described more fully in the claims that follow thereafter. 
In accordance with Scheme I, wherein P is hydrogen or a protecting group such as benzyl (Bn) or BOC (t-butyloxycarbonyl), Xxe2x80x2 is O or S, R2a is selected from hydrogen, alkyl, and alkyl substituted with one or more groups selected from cycloalkyl, halogen, hydroxy, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, and unsubstituted or substituted aryl, xe2x80x94C(O)ORe, ORe, xe2x80x94OC(O)Re, xe2x80x94C(O)NReRf, R2b is selected from alkyl substituted with one or more xe2x80x94N(Re)C(O)NRf, xe2x80x94NReC(O)Rf, xe2x80x94NHC(NH)NReRf or, i is an integer from 1 to 8, and A, m, n, R1, R2, R3, R4, R5, Rc, and Rd are as described hereinabove, benzimidazol-2-ones 2, can be prepared from diamines 1 (which, when A is aryl, may be made by known methods: e.g., J. Med. Chem. 30, 814-819 (1987)), using known conditions and procedures. When A is heteroaryl, compound 1 can be prepared by reductive amination of the 2-nitro heteroarylamines that are known or can be prepared using known procedures (e.g., Heterocycles 38, 529-540 (1994), Arch. Pharm. 314, 564-567 (1981), JACS, 78, 242 (1956)) with commercially available BOC or benzyl protected 4-piperdone followed by reduction of the nitro group under palladium catalyzed hydrogenation reaction conditions. The intermediate 2 can then be heated with an alkyl, benzyl, or dialkylaminoalkyl halide in the presence of a base such as potassium carbonate, cesium carbonate or sodium hydride in a solvent such as dimethyl formamide (DMF), tetrahydrofuran (THF) or acetone to give the corresponding compounds of 3a. 2 can also be treated with a protected phthalimidoalkyl halide or a chloroalkyl halide to give the corresponding compounds of 4 and 5a. The chloride of compound 4 can be further displaced with mono- or di-substituted amines or cyclic amines to give the corresponding compounds of 6a.
The intermediates 3a, 5a, or 6a can be treated with trifluoroacetic acid to remove the protecting group P (P can be either benzyl or BOC) or with xcex1-chloroethylchloroformate or under a hydrogenation condition to remove a benzyl protecting group. This forms the intermediates 3b, 5b, or 6b, respectively. The piperidine nitrogen can then be substituted by treatment with substituted isocyanates or substituted isothiocyanates in an appropriate solvent such as acetonitrile, tetrahydrofuran or methylene chloride to give products Ia, Ib1, and Ic, respectively, wherein Y is O. Compounds Ia, Ib1 and Ic wherein Y is O can then be converted to Ia, Ib1 and Ic wherein Y is S by treatment with P2S5 with a base such as potassium hydroxide in an appropriate solvent such as toluene or benzene. In cases where the isocyanates or isothiocyanates are not commercially available, they can be prepared by treating the appropriate amines with reagents such as phosgene, thiophosgene or di-2-pyridylthionocabonate. Compound Ib1 can be further treated with hydrazine in solvents such as ethanol (EtOH), methanol (MeOH), or THF to give the free amine Ib2. The amine Ib2 can then be acylated by the addition of acylhalides or anhydrides to give compounds Id. Compound 3b, 5b or 6b can be dissolved in an appropriate solvent such as DMF or THF then heated in the presence of 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea to afford a substituted guanidinyl intermediate 7. This intermediate 7, dissolved in a solvent such as DMF or THF, can be treated with alkyl or aryl halides under basic conditions (such as in NaH or KH) then treated with trifluoroacetic acid to remove the BOC groups to give compounds Ie wherein either m or n is 1, or R3 is selected from hydrogen, alkyl, substituted alkyl, benzhydryl, heterocyclyl, substituted heterocyclyl, xe2x80x94C(O)ORc, and xe2x80x94C(O)NRcRd. 
In accordance with Scheme II, wherein Z is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl, Zxe2x80x2 is 
and A, Y, m, n, R1, R2, R3, R4, and R5 are as described above, compounds of formula If can be prepared by heating compound 3b, 5b, or 6b with the appropriate substituted isothiouronium salt 8 (prepared as described in J. Med. Chem. 43, 2362-2370 (2000)) and triethylamine in a solvent such as DMF, THF or acetonitrile. Compounds 3b, 5b, or 6b can also be added to substituted thiourea 9, prepared by reacting sodium cyanamide with the corresponding isothiocyanate, in the presence of a water soluble carbodiimide such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and an appropriate solvent such as DMF and ethanol (procedure described in Tetrahedron Letters, 30, 7313-7316 (1989), to form corresponding compounds of Ig.
The method of treating conditions associated with vasopressin receptor or Neuropeptide Y receptor activity described in the present invention may be carried out using a pharmaceutical composition comprising any of the compounds as defined herein and a pharmaceutically acceptable carrier. The pharmaceutical composition may contain between about 100 mg and 1000 mg, preferably about 100 to 500 mg, of the compound, and may be constituted into any form suitable for the mode of administration selected. Carriers include necessary and inert pharmaceutical excipients, including, but not limited to, binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms, such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release formulations), granules, and powders, and liquid forms, such as solutions, syrups, elixers, emulsions, and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
Advantageously, compounds of the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders; lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
The liquid forms can be in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methylcellulose and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous administration is desired.
The compound of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
Compounds of the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The compounds of the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyl eneoxidepolylysine substituted with palmitoyl residue. Furthermore, the compounds of the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyeric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.
Compounds of this invention may be administered in any of the foregoing compositions and according to dosage regimens established in the art whenever treatment of disorders of vascular resistance is required.
The daily dosage of the products may be varied over a wide range from 100 to 3000 mg per adult human per day. For oral administration, the compositions are preferably provided in the form of tablets containing the active ingredient in the amount sufficient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 1 mg/kg to about 30 mg/kg of body weight per day. Preferably, the range is from about 3 to about 15 mg/kg of body weight per day, most preferably, from about 5 to about 10 mg/kg of body weight per day. The compounds may be administered on a regimen of 1 to 2 times per day.
Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular compound used, the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
The following examples are intended to illustrate the invention but not to limit it. Melting point determinations were done on a Thomas-Hoover capillary melting point apparatus and are uncorrected. Nuclear magnetic resonance (1NMR) spectra were recorded on a Bruker AC300 (300 MHz) spectrometer. Chemical shifts are reported in parts per million (d) downfield relative to tetramethylsilane as standard. Mass spectra (m/z) were obtained on a HP 1100 LC/MSD.